Genotype-phenotype associations of polymorphisms within the gene locus of NOD-like receptor pyrin domain containing 3 in Swiss inflammatory bowel disease patients

Abstract

Background: Genetic variations within the regulatory region of the gene encoding NOD-like receptor pyrin domain containing 3 (NLRP3) have been associated with Crohn's Disease (CD). NLRP3 is part of the NLRP3-inflammasome that mediates the maturation of IL-1β and IL-18. Carrying the major allele of the single nucleotide polymorphisms (SNPs) rs10733113, rs4353135 and rs55646866 is associated with an increased risk for CD. We here studied the impact of these polymorphisms on clinical characteristics in patients of the Swiss IBD Cohort Study (SIBDCS).

Methods: We included 981 Crohn's disease (CD) patients and 690 ulcerative colitis (UC) patients of the SIBDCS. We analyzed whether three CD-associated NLRP3 polymorphisms have an impact on the clinical disease course in these patients.

Results: In CD patients presence of the major allele (G) of rs10733113 was associated with less surgeries and lower maximal CDAI and a similar trend was observed for rs55646866 and rs4353135. Presence of the major allele of all three SNPs was negatively correlated to maximal CDAI. In UC patients homozygous genotype for the major allele (CC) for rs55646866 was associated with a higher age at diagnosis and a higher MTWAI index. Homozygous genotype for the major allele of all three polymorphisms was associated with a higher number of ambulatory visits and longer hospital stays.

Conclusions: In CD patients presence of the major allele of all three polymorphisms was associated with markers of a less severe disease course, while in UC the homozygous genotype for all major alleles suggested a more severe disease activity.

Keywords: Clinical characteristics; Inflammatory bowel disease; NLRP3 inflammasome; Single nucleotide polymorphisms.

Fig. 1

Effect of the major alleles of rs10733113, rs4353135 and rs55646866 on clinical parameters in CD patients. The graphs show median Log (max. CDAI) values for maximal CDAI within the 25% and 75% percentile (box borders) and outliers (dots) in CD patients A homozygous for the major allele, heterozygous or homozygous for the minor allele for rs10733113, rs4353135 and rs55646866, B depending on the cumulative genetic risk score for carrying the major allele for rs1073313, rs4353135 and rs55646866. In a linear regression model, a significant negative correlation between the cumulative genetic score and log (max. CDAI) can be observed (Coefficient − 0.097; 95% CI − 0.182 to − 0.011; p = 0.026) C CD duration in months within the 25% and 75% percentile (box borders) and outliers (dots) and D percentage of patients with stenosis that required an operation for treatment of stenosis in CD patients homozygous for the major allele, heterozygous or homozygous for the minor allele for rs10733113, rs4353135 and rs55646866

Fig. 2

Individual and cumulative effect of the major alleles of rs10733113, rs4353135 and rs55646866 on ambulatory flare management in UC patients. The graphs show the percentage of UC patients with at least one ambulatory visit for flare management A Homozygous for the major allele, heterozygous or homozygous for the minor allele for rs10733113, rs4353135 and rs55646866. B Depending on the cumulative genetic risk score for carrying the major allele for rs10733113, rs4353135 and rs55646866. In a linear regression model a significant association between the cumulative genetic score and the percentage of patients needing ambulatory flare management could be observed (Odds ratio 2.081; 95% CI − 1.393 to 3.11; p < 0.001). C Age at disease onset is shown within the 25% and 75% percentile (box borders) and outliers (dots) in UC patients.